The objective of this study is to develop a methodology for sampling DNA from skin to assess the risk of UV-induced skin cancer development. Our goal is to establish non-invasive biomarker sampling from skin for a variety of systemic and cutaneous diseases. Here, we will focus on measurement of UV-induced DNA mutations that are linked to all skin cancers, both non-melanoma skin cancers and melanoma alike. Our central hypothesis is that the non- invasive collection and mutational analysis of DNA from clinically-normal skin correlates with the level of risk for skin cancer. We will demonstrate this in a mouse model of UV-induced skin cancer using our novel methods. Our specific aims are: Specific Aim 1: Optimize ultrasound-assisted sampling of DNA from skin. We will first assess the optimal ultrasound (intensity, duty cycle and exposure time) and microdermabrasion (contact roughness and oscillation frequency) parameters to maximize the total amount of DNA extracted from the skin. We will also optimize the chemistry of the sampling medium (liquid used to couple mechanical energy to the skin) to maximize the amount and stability of collected DNA using a combinatorial library of surfactants chosen from four categories (cationic, anionic, zwitterionic and non-ionic surfactants). Our goal is to harvest at least 5 ug DNA per sq. cm of skin and ensure its stability (>80%) for 4 hours. Specific Aim 2: Evaluate the safety of the sampling process. We will perform detailed histopathology assessment of sampled skin to determine the effect of ultrasound on skin structure. Recovery kinetics of skin after sampling will be assessed. Our target is recovery of skin within 7 days based on histology. Specific Aim 3: Validate the use of UV mutational load in skin as a biomarker of skin cancer risk. Using chronically UV-irradiated Hairless mice, we will characterize the burden of UV signature mutations in skin following ultrasonic DNA extraction at multiple time points following irradiation We will test whether DNA collected from chronically UV-exposed skin by ultrasound can be used to measure the UV-induced mutation burden in terms of DNA photoproducts (thymine dimers), UV signature lesions in particular susceptible genes (Tp53, Hras, Kras, Ink4a), and UV signature mutations across the entire exome.